Acetylcholine Receptor (AChR)-binding Antibodies

Myasthenia gravis (MG) is an acquired disorder of neuromuscular transmission that is characterized by skeletal muscle weakness and fatigability on exertion that is exacerbated by repeated muscle activity.^2-7 This autoimmune disease is caused by antibodies directed toward receptors embedded in the motor endplate of the neuromuscular junction. Progressive weakness of the ocular muscles manifesting as asymmetric ptosis and variable diplopia are the presenting symptoms in 60% of patients.^5,7 Many patients progress to more generalized weakness of peripheral limb muscles and muscles required for body posture, including facial and neck muscles. Bulbar muscle weakness compromises speaking (dysarthria), chewing and swallowing (dysphagia) and respiratory muscle weakness can lead to a myasthenic crisis where patients need to be ventilated artificially.⁸ Clinical symptoms may be restricted to one muscle group, in particular the eye muscles (ocular MG), or may become generalized (generalized MG).^5-8

Patients with MG frequently have thymic abnormalities (thymic hyperplasia or thymoma).⁹ Ten to 15 percent of patients with MG patients have thymoma, and up to 50% of thymoma patients develop MG.⁹ It is thought that the thymus plays a role in MG pathogenesis and these patients respond well to the surgical removal of the thymus gland.¹⁰

Neonatal MG can occur as a result of trans-placental transit of antibodies from an affected mother to the fetus, or in some cases, due to antibody to the fetal form of AChR.^11-13 In the latter case, the mother may be unaffected. It should be noted that the AChR antibody assays employed by Labcorp contain a mixture of adult and embryonic AChRs allowing for the detection of autoantibodies to both proteins. In most cases affected babies are born with a diminished ability to suck and generalized hypotonia. Decrease in utero feta movement caused by MG can also result in arthrogryposis multiplex congenital, a condition where the neonate suffers from contractures in more than two joints and in multiple body areas.

The majority of patients with MG have antibodies to the acetylcholine receptor (AChR) and, less frequently, to the other proteins at postsynaptic membrane of the neuromuscular junction.^14-16 AChR antibodies impede neuromuscular transmission by a range of pathogenic mechanisms including the alteration of tissue architecture and/or by causing a reduction the density of functionality of AChRs.^1,17-21 Three functionally different types of antibodies against muscle AChR can be measured.^1,21-24

• AChR binding antibodies attach to the AChR activate the complement system result in in destruction and focal lysis of the neuromuscular junction leading to the destruction of AChR and AChR-related protein at the end-plate.^1,20

• AChR blocking antibodies functionally block the binding of the neurotransmitter acetylcholine to the receptor.²⁰ These antibodies usually occur in association with AChR-binding antibodies and have a higher prevalence in generalized MG compared with ocular MG.²⁰

• AChR modulation antibodies crosslink receptor subunits in such as way as to cause the receptors to be internalized and degraded in a process known as antigenic modulation.^20,22,25-27 Modulating antibodies are implicated with an increased risk of thymoma and the majority of patients with thymoma have modulating antibodies.²⁸

Test for serum autoantibodies are highly sensitive and specific for generalized MG but lack sensitivity when there is pure ocular involvement.^1,14,29-30 Approximately 85% of patients with generalized MG have detectable muscle AChR antibodies (of one or more types), while fewer patients with ocular MH have the antibodies (50-60%).^4,30 In general, an elevated level of any one of the AChR-binding antibodies in a patient with compatible clinical features confirms the diagnosis of MG. Approximately 15 percent of individuals with confirmed myasthenia gravis have no measurable AChR binding, blocking, or modulating antibodies. Thirty-five percent of these patients (six percent of all MG patients) will have antibodies directed against a muscle-specific tyrosine kinase (MuSK).^10,31 Autoantibodies levels do not generally correlate with disease severity. However, in individual patients, serial antibody titers tend to correlate with disease status.^18,19,32-34

Autoantibodies directed against the contractile elements of striated muscle are found in 30% of adult patients with myasthenia gravis and in 80% of those with thymoma.^35-37 Striational antibodies are associated with the late-onset MG subgroup and are rarely found in AChR antibody-negative MG.